Hypercholesterolemia is known to be one of the prime risk factors for atherosclerosis and coronary heart disease, the leading cause of death and disability in Western countries.
There are agents known, however, that are very active antihypercholesterolemic agents which function by limiting cholesterol biosynthesis via inhibiting the enzyme, HMG-CoA reductase. These agents include the natural fermentation products, such as mevastatin, lovastatin and pravastatin, and semisynthetic analogs, such as simvastatin.
Numerous analogs and homologs of these compounds have been described in the patent literature. U.S. Patent No. 4,444,784 discloses analogs of lovastatin which possess polyhydronaphthyl moieties and various 8-acyloxy groups attached thereto. U.S. Pat. No. 4,444,784 also discloses numerous pharmaceutically acceptable salts of these analogs of lovastatin wherein the 8-acyloxy group has been elaborated broadly. The pharmaceutically acceptable salts disclosed therein include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)aminomethane (hereinafter called "tromethamine"), and tetramethylammonium hydroxide.
U.S. Pat. No. 4,661,483 also discloses analogs of lovastatin wherein the 8-acyloxy group has been elaborated. Additionally, co-pending U.S. applications Ser. Nos. 859,513, now abandoned, 859,524, now abandoned 859,525, now U.S. Pat. No. 4,766,245, 8/23/88, 859,530now abandoned 859,534, now abandoned and 859,535 now U.S. Pat. No. 4,770,871, 9/13/88 all filed on May 5, 1986, disclose further analogs of lovastatin which have functionalized 8-acyloxy groups.
Co-pending U.S. patent application, Ser. No. 092 2, 1987, discloses compounds which are analogs of lovastatin and related compounds which possess a methyl group in the 6-position in the 6.beta. stereochemical position.
Co-pending U.S. patent application, Ser. No. 048,136, now abandoned filed May 15, 1987, discloses compounds which are analogs of lovastatin and related compounds which possess a hydroxymethyl group, acyloxymethyl group, carbamoyloxymethyl group, a carboxy group, an alkoxycarbonyl group or a carbamoyl group substituted on the 6-position of the polyhydronaphthyl moiety.
Co-pending U.S. patent application, Ser. No. 092,353,now abandoned filed Sept. 2, 1987, discloses analogs of lovastatin and related compounds which possess a hydroxyalkyl group, acyloxyalkyl or carbamoyloxyalkyl group or a ketone group substituted on the 6-position of the polyhydronaphthyl moiety.
Co-pending U.S. patent application, Ser. No. 142,377now U.S. Pat. No. 4,857,547, 8/15/89 filed Jan. 7, 1988, discloses analogs of lovastatin and related compounds which contain two double bonds in the 4,4a- and 5,6- positons or a double bond at the 5,6- position of the polyhydronaphthyl moiety.
MEVACOR.RTM., which contains lovastatin as the active agent, and ZOCOR.RTM., which contains simvastatin as the active agent, are now commercially available for use as antihypercholesterolemic drugs. While these products are scientific breakthroughs and remarkably safe and effective, the reduction of the effective dosage amount which is anticipated to diminish the low incidence of adverse experiences associated which these drugs would be extremely beneficial in view of the lifetime regimen of treatment of hypercholesterolemia.
Antihypercholesterolemic agents are useful for the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia and like diseases in humans. They may be administered orally or parenterally in the form of a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 2000 mg (preferably 10 to 100 mg) which may be given in two to four divided doses. Higher doses may be favorably employed as required.
The need for systems that can deliver a drug at a controlled rate to a variable environment (e.g. gastrointestinal tract) of use over a specified period of time is well established. The use of novel, charged, water-insoluble, non-diffusable resinous powders to modulate drug release from osmotically sensitive devices with rate-controlling semipermeable walls that are permeable to water and substantially impermeable to dissolved solutes has not been disclosed in the prior art and represents an advance in drug delivery technology and device composition.
U.S. Pat. Nos. 3,854,770 and 3,916,899 disclose devices which have semipermeable walls that are permeable to water and substantially impermeable to dissolved drugs and solutes. A passageway through the semipermeable wall, disclosed as a drilled hole, is provided as an exit portal for the drug through the wall. U.S. Pat. Nos. 4,256,108; 4,160,452; 4,200,098 and 4,285,987 disclose devices which contain multiple wall layers, at least one of said walls having a drilled hole for the release of core components through a rate-controlling semipermeable membrane that is substantially impermeable to dissolved drugs and other solutes. The use of charged resins to modulate drug release from the above devices was not disclosed.
Devices for the controlled and continuous delivery of an active agent made from microporous materials are known to the prior art. Generally, the agent is embedded in or surrounded by the material and its release therefrom often is adversely influenced by external conditions. U.S. Pat. No. 3,538,214 discloses a device consisting of drug coated with a film of water-insoluble plastic containing a modifying agent that is soluble at a certain pH. When this device is in the gastro-intestinal tract, the modifying agent is partially or fully dissolved from the film by gastrointestinal fluid to form a porous film. This lets fluid through the film to dissolve the drug and leach it outwards through the pores into the tract. Controlled release is difficult to achieve with this device because the selection of the modifying agent is based on the unknown acid and alkaline state of the gastro-intestinal tract which concomitantly influences pore formation and the exposure of drug to fluid. A similar device is disclosed in U.S. Pat. No. 2,928,770. The device of this patent consists of an outer layer of drug coated onto a porous material having its pores filled with a softened wax that is supposedly removed in the gastrointestinal tract by the alimentary fluid. This device cannot be relied on for controlled release because it too requires in situ pore formation which is dominated by unregulated external conditions and not by the device. The use of pore formers in substantially water impermeable polymers is disclosed in J. Pharm. Sci. 72, p. 772-775 and U.S. Pat. Nos. 4,244,941; 4,217,898; and 3,993,072. These devices release the core components by simple diffusion. U.S. Pat. No. 3,957,523 discloses a device which has a pH sensitive pore former in the device wall. U.S. Pat. Nos. 4,309,996; 4,320,759; 4,235,236 disclose layered devices with a microporous coat containing a drug layer and a swelling polymer layer acting as the driving force for delivery of agents. The use of charged resins to modulate drug release from the above devices was not disclosed.
U.S. Pat. No. 4,221,778 discloses ion-exchange resin drug complexes as delivery devices where the resin and drug carry opposite charges and osmotic factors are not included; drug release is actuated by exchange of the drug with another ion which dislodges the drug from the resin.